Alzheimer's Disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly. In 1984, Blass and Zemcov (Blass and Zemcov 1984) proposed that AD resulted from a decreased metabolic rate in sub-populations of cholinergic neurons. Measurements of cerebral glucose metabolism indicate that glucose metabolism is reduced 20-40% in AD resulting in critically low levels of ATP.
Attempts to compensate for reduced cerebral metabolic rates in AD have met with some success. Elevation of serum ketone body levels in AD patients raises cognitive scores (Reger, Henderson et al. 2004) and USP.
Parkinson Disease (PD)
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is the second most common neurodegenerative disease after Alzheimer's disease. The estimated prevalence of PD is 0.3 percent in the general U.S. population and a prevalence of 4 to 5 percent in those older than 85 years. PD is characterized by motor abnormalities, including tremors, muscle stiffness, lack of voluntary movements, and postural instability. A primary neuropathological feature of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of eosinophilic intracytoplasmic inclusions (Lewy bodies) in the residual dopaminergic neurons.
Therefore, there exists a need for more effective treatments for PD and in particular for treatments that are neuroprotective.
While the cause of sporadic PD is uncertain, several lines of evidence suggest that defects in oxidative phosphorylation may contribute to its pathogenesis. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), blocks complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial electron transport chain, and causes the loss of dopaminergic neurons and the typical symptoms of PD. Reduction in complex I activity has also been reported in PD tissues. This defect is not confined only to the brain but has also been found in platelets from PD patients.
D-beta-Hydroxybutyrate (BHB) is a ketone body produced by hepatocytes and, to a lesser extent, by astrocytes. BHB acts as an alternative source of energy in the brain when glucose supply is limited such as during starvation. BHB has been found to protect from MPTP-related complex I inhibition, by enhancing oxidative phosphorylation (Tieu, 2003).
Friedreich's Ataxia (FRDA)
FRDA is a recessive disease characterized by progressive ataxia, hypertrophic cardiomyopathy, early onset of insulin-resistant diabetes, invalidism, and premature death. FRDA is a genetic disorder caused by a deficiency of frataxin, a 210 amino acid nuclear-encoded mitochondrial protein. Low levels of the protein are due to the expansion of an intronic GAA repeat, leading to decreased mRNA levels. FRDA patients show a decrease in the activity of the mitochondrial enzyme aconitase. Aconitase is responsible for conversion of citrate to isocitrate, the first step in the Krebs (also known as the citric acid or TCA cycle). Deficiency of frataxin in human patients is thought to lead primarily to defects in the TCA cycle.
Recent work shows that elevation of blood ketone bodies, a normal response to fasting, can increase mitochondrial citrate and isocitrate levels, thus overcoming the block in aconitase found in FRDA. A ketone body-based therapy could provide an effective treatment for this group of patients.
GLUT1-deficient Epilepsy
GLUT1-deficient Epilepsy is characterized by infantile seizures, delayed development, and acquired microcephaly with mental retardation. GLUT1-deficient epilepsy results from several types of mutation in the gene of GLUT1. Glucose transporter 1 (GLUT1) is the major protein responsible for the transport of glucose from bloodstream into the brain. Under standard dietary conditions, the brain is almost entirely dependent upon blood glucose for energy. However, under some circumstances, such as starvation, ketone bodies can provide a source of energy different from glucose. Ketone bodies do not rely on GLUT1 for transport into the brain and therefore may provide energy in GLUT1-deficient syndrome. Ketone body therapy may therefore become a practical method for lifelong treatment of these patients.
Leprechaunism and Rabson-Mendenhall Syndrome
Leprechaunism and Rabson-Mendenhall syndrome are rare disease characterized by insulin resistance, persistent hyperglycemia and retardation of growth. Subjects rarely survive past 20 years of age. These syndromes result from mutations in the insulin receptor gene, which lower the receptors affinity for insulin. The current treatment consists of administration of increasing doses of insulin (up to several thousand units per day). This treatment yields only weak results due to the poor binding of insulin to its receptor. Ketone bodies have been shown to mimic the effects of insulin's stimulation of the PDH multienzyme complex, thereby increasing the Krebs TCA cycle metabolite levels, increasing the energy output in the form of ATP, and enhancing metabolic efficiency. A ketone-rich, or ketogenic diet may prove an effective treatment of these conditions.
Age-Associated Memory Impairment
Aging causes deterioration of various aspects of physiology in normal adults, including memory performance. Such age related declines in cognitive performance have long been recognized by medical practitioners. Impairment of memory performance in the elderly has been detected in several standard memory tests, including the Wechsler Memory Scale (WMS) and immediate and delayed Visual Reproduction Test (Trahan et al. Neuropsychology, 1988 19(3) p. 173-89), the Rey Auditory Verbal Learning Test (RAVLT) (Ivnik, R. J. et al. Psychological Assessment: A Journal of Consulting and Clinical Psychology, 1990 (2): p. 304-312) and others (for review see Larrabee and Crook, Int. Psychogeriatr, 1994 6(1): p. 95-104.
Other Diseases and Syndromes
A great number of other diseases and syndromes are associated with decreased metabolism. Such conditions include Coronary Arterial Bypass Graft (CABG) dementia, anesthesia induced memory loss, Huntington's disease and many other. It is apparent that a metabolic intervention may aid people suffering from such afflictions.
There is thus a need in the art to develop compositions and methods for the treatment and/or prevention of cognitive impairment, particularly in aging or geriatric mammals such as humans.
Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. A partial list of those patents and applications referenced herein include, for example, U.S. Ser. No. 60/953,074, “Genomic testing in Alzheimer's disease and other diseases associated with reduced neuronal metabolism”, filed Jul. 31, 2007; U.S. Ser. No. 60/917,886, “Inhibitors of Acetyl-CoA Carboxylase for Treatment of Hypometabolism”, filed May 14, 2007; U.S. Ser. No. 11/123,706, “Method for Reducing Levels of Disease Associated Proteins”, filed May 3, 2005; U.S. Ser. No. 11/424,429, “Method To Reduce Oxidative Damage And Improve Mitochondrial Efficiency”, filed Jun. 15, 2006; U.S. Ser. No. 10/546,976, “Novel-Chemical Entities and Methods for their Use in Treatment of Metabolic Disorders”, filed Aug. 25, 2005; U.S. Ser. No. 09/845,741, filed May 1, 2001; U.S. Ser. No. 10/152,147, filed Dec. 28, 2004, now U.S. Pat. No. 6,835,750; U.S. Ser. No. 11/021,920, filed Dec. 22, 2004; U.S. Ser. No. 11/331,673, filed Jan. 13, 2006; U.S. Ser. No. 11/611,114, filed Dec. 14, 2006; and U.S. Ser. No. 11/771,431, filed Jun. 29, 2007.